Tumor-associated macrophages (TAM) play a controversial role in epithelial-mesenchymal transition (EMT) and prognosis of colorectal cancer (CRC). In particular, the microlocalization, polarization and prognostic impact of TAM in the immediate environment of invading CRC cells has not yet been established. To address this clinically relevant question, intraepithelial (iCD68) and stromal macrophages (sCD68), M1-macrophages (iNOS), M2-macrophages (CD163), cytokeratin-positive cancer cells (tumor buds) and expression of the anti-phagocytic marker CD47 were investigated in primary tumors of 205 well-characterized CRC patients. Cell-to-cell contacts between tumor buds and TAM were detected using high-resolution digital scans. The composition of the tumor microenvironment was analyzed with clinicopathological and molecular features. High CD68 counts predicted long term overall survival independent of microlocalization (iCD68 p=0.0016; sCD68 p=0.03), pT, pN, pM and post-operative therapy. CD68 infiltration correlated with significantly less tumor budding (iCD68 p=0.0066; sCD68 p=0.0091) and absence of lymph node metastasis (sCD68 p=0.0286). Cell-to-cell contact of sCD68 and invading cancer cells was frequent and ameliorated the detrimental prognostic effect of the tumor budding phenotype. Subgroup analysis identified long-term survival with CD47 loss and predominance of CD163 M2 macrophages ( = 0.0366). CD163 macrophages represented 40% of the total population, and positively correlated with total CD68 macrophage numbers (r[CD68/CD163] = 0.32; = 0.0001). Strong CD163 infiltration predicted lower tumor grade ( = 0.0026) and less lymph node metastasis ( = 0.0056). This study provides direct morphological evidence of an interaction between TAM and infiltrating cancer cells. The prognostic impact of TAM is modulated by phenotype, microlocalization and the expression of anti-phagocytic markers in CRC.

HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis. ' UICCKey words: HOXD13; HOX and multitumor tissue microarray; HOXD13 and pancreas Class I Homeobox genes (Hox, mice; HOX, human) are transcription factors mostly involved in embryonic development. 1 They display an unique genomic network organization: 4 compact chromosomal loci (HOXA at 7p15.3, HOXB at 17q21.3, HOXC at 12q13.3 and HOXD at 2q31 2 ) where 39 sequence corresponding genes can be aligned with each other into 13 antero-posterior paralogous groups. The HOX gene network, the most repeat-poor regions in the human genome, 3 is also expressed in normal adult human organs. 4 HOX genes appear to regulate phenotype cell identity, 5,6 cell differentiation 7,8 and control primary cellular processes, as proven by the description of congenital, 9 somatic 10 and metabolic 11 diseases involving these genes. Furthermore, besides the already established role of the HOX network in hematopoiesis and leukemogenesis, 12 HOX genes are implicated in the neoplastic alterations of human solid tissues and organs such as kidney, colon, lung, skin, bladder, liver, breast and prostate. 13,14 New crucial functions have recently been ascribed to HOX genes and homeoproteins mostly related to their interaction with miRNAs and ncRNAs to guarantee transcription and export of specific mRNAs. 15,16 Locus D HOX genes are localized on chromosome 2q31-32 and play a role, with its posterior paralogous genes, in limb and digit generation during embryonic development 1...

One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.

Adjuvant chemotherapy with one cycle of modified-BEP is a feasible and safe treatment of patients with CS I NSGCT at high risk of relapse. In these patients, it appears to be an alternative to two cycles of BEP and to have a lower relapse rate than retroperitoneal lymph node dissection. If confirmed by other centers, 1 cycle of adjuvant BEP chemotherapy should become a first-line treatment option for this group of patients.

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